US2024166623A1PendingUtilityA1
Novel process
Est. expiryFeb 7, 2041(~14.6 yrs left)· nominal 20-yr term from priority
Inventors:Martin Lee StockleyRobert Andrew HealdDavid Charles LathburyPingao YangQinjin WangYanjie FuMark Theodoor VerhaarFuxu LiaoJohn LiddonMatthew LloydTang XiaopingZarrin AnsariStephen Keen
C07D 401/04C07C 211/48C07D 207/12C07B 2200/05C07D 493/04A61P 35/00C07C 209/10C07C 211/52A61K 31/4439C07D 491/056C07D 317/20
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Claims
Abstract
The invention relates to a process for preparing heterocyclic amide derivatives, to novel polymorphic forms obtained from said process and the use of said polymorphic forms for use in the treatment and prophylaxis of cancer.
Claims
exact text as granted — not AI-modified1 . A process for preparing a compound of formula (I):
which comprises treating a compound of formula (XX):
with a Lewis acid in the presence of a scavenger agent.
2 . The process according to claim 1 , wherein the scavenger agent is a diol containing moiety.
3 . The process according to claim 2 , wherein the diol containing moiety is selected from ethylene glycol, glycerol, 2,3-butanediol or meso-erythritol, in particular meso-erythritol.
4 . The process according to any one of claims 1 to 3 , wherein the Lewis acid is boron trifluoride (BF 3), such as boron trifluoride diethyl etherate.
5 . A process for preparing a compound of formula (I):
which comprises the following steps:
6 . A process for preparing a hemihydrate compound of formula (I), i.e. a compound of formula (IB):
which comprises the following steps:
7 . A compound of formula (I) obtainable from the process as defined in any one of claims 1 to 6 .
8 . The compound of formula (I) according to claim 7 , which is (2S,3S,4S)-N-(5-Chloro-2,4-difluorophenyl)-3,4-dihydroxy-N-(methyl-d3)-1-(6-methyl-4-(trifluoromethyppyridin-2-yl)-5-oxopyrrolidine-2-carboxamide (Form A) (Example 1).
9 . The compound of formula (I) according to claim 8 , which is characterised by any one or more of the following parameters:
(i) an XRPD pattern substantially as shown in FIG. 1 ; (ii) peaks at the same diffraction angles (2θ) of the XRPD pattern shown in FIGS. 1 and optionally wherein the peaks have the same relative intensity as the peaks shown in FIG. 1 ; (iii) major peaks at diffraction angles (2θ) and intensities as those shown in the XRPD pattern in FIG. 1 ; (iv) an XRPD pattern having peaks at 6.9±0.5°, 7.6±0.5°, 9.5±0.5°, 11.4±0.5°, 13.7±0.5°, 20.1±0.5°, 20.7±0.5° and 22.6 (20, 1d.p); (v) an XRPD pattern having peaks at 6.9±0.2°, 7.6±0.2°, 9.5±0.2°, 11.4±0.2°, 13.7±0.2°, 20.1±0.2°, 20.7±0.2° and 22.6±0.2° (20, 1d.p); (vi) an XRPD pattern having peaks at 6.9±0.1°, 7.6±0.1°, 9.5±0.1°, 11.4±0.1°, 13.7±0.1°, 20.1±0.1°, 20.7±0.1° and 22.6±0.1° (20, 1 d.p); (vii) an XRPD pattern having peaks at 6.9, 7.6, 9.5, 11.4, 13.7, 20.1, 20.7 and 22.6 (20, 1 d.p); (viii) an XRPD pattern having peaks as set out in the below table:
Relative intensity,
Angle, °2θ
%*
6.9
94.7
7.6
24
9.5
62.5
11.4
100
13.7
38
20.1
51.4
20.7
23.1
22.6
27.4
*Peaks with relative intensity of less than 20% are not reported;
(ix) a differential scanning calorimetry (DSC) onset temperature of 182.26° C.±0.5° C. (such as 182.26° C.±0.2° C., in particular 182.26° C.±0.1° C., more particularly 182.26° C.);
(x) a differential scanning calorimetry (DSC) peak temperature of 182.54° C.±0.5° C. (such as 182.54° C.±0.2° C., in particular 182.54° C.±0.1° C., more particularly 182.54° C.);
(xi) a differential scanning calorimetry (DSC) thermogram as depicted in FIG. 2 ;
(xii) a thermogravimetric peak mass loss at a temperature of 231.7° C.±0.5° C. (such as 231.7° C.±0.2° C., in particular 231.7° C.±0.1° C., more particularly 231.7° C.); and/or
(xiii) a thermogravimetric analysis (TGA) thermogram as depicted in FIG. 3 .
10 . The compound of formula (I) according to claim 7 , which is (2S,3S,4S)-N-(5-Chloro-2,4-difluorophenyl)-3,4-dihydroxy-N-(methyl-d3)-1-(6-methyl-4-(trifluoromethyppyridin-2-yl)-5-oxopyrrolidine-2-carboxamide hemihydrate (Form B) (Example 2), i.e. a compound of formula (IB).
11 . The compound of formula (IB) according to claim 10 , which is characterised by any one or more of the following parameters:
(i) an XRPD pattern substantially as shown in FIG. 4 ; (ii) peaks at the same diffraction angles (2θ) of the XRPD pattern shown in FIGS. 4 and optionally wherein the peaks have the same relative intensity as the peaks shown in FIG. 4 ; (iii) major peaks at diffraction angles (2θ) and intensities as those shown in the XRPD pattern in FIG. 4 ; (iv) an XRPD pattern having peaks at 5.1±0.5°, 8.7±0.5°, 10.1±0.5°, 12.2±0.5°, 12.7±0.5°, 14.2±0.5°, 15.1±0.5°, 16.5±0.5°, 17.1±0.5°, 18.8±0.5°, 20.2±0.5°, 22.4±0.5° and 22.9±0.5° (20, 1d.p); (v) an XRPD pattern having peaks at 5.1±0.2°, 8.7±0.2°, 10.1±0.2°, 12.2±0.2°, 12.7±0.2°, 14.2±0.2°, 15.1±0.2°, 16.5±0.2°, 17.1±0.2°, 18.8±0.2°, 20.2±0.2°, 22.4±0.2° and 22.9±0.2° (20, 1 d.p); (vi) an XRPD pattern having peaks at 5.1±0.1°, 8.7±0.1°, 10.1±0.1°, 12.2±0.1°, 12.7±0.1°, 14.2±0.1°, 15.1±0.1°, 16.5±0.1°, 17.1±0.1°, 18.8±0.1°, 20.2±0.1°, 22.4±0.1° and 22.9±0.1° (20, 1 d.p); (vii) an XRPD pattern having peaks at 5.1, 8.7, 10.1, 12.2, 12.7, 14.2, 15.1, 16.5, 17.1, 18.8, 20.2, 22.4 and 22.9 (20, 1d.p); (viii) an XRPD pattern having peaks as set out in the below table:
Relative intensity,
Angle, °2θ
%*
5.1
84.4
8.7
24.7
10.1
100.0
12.2
66.4
12.7
32.3
14.2
27.0
15.1
25.8
16.5
36.4
17.1
22.0
18.8
26.7
20.2
28.0
22.4
24.3
22.9
48.7
*Peaks with relative intensity of less than 20% are not reported.
(ix) a differential scanning calorimetry (DSC) onset temperature of 80.25° C.±0.5° C. (such as 80.25° C.±0.2° C., in particular 80.25° C.±0.1° C., more particularly 80.25° C.);
15 (x) a differential scanning calorimetry (DSC) peak temperature of 95.02° C.±0.5° C. (such as 95.02° C.±0.2° C., in particular 95.02° C.±0.1° C., more particularly 95.02° C.);
(xi) a differential scanning calorimetry (DSC) thermogram as depicted in FIG. 5 ;
(xii) a thermogravimetric peak mass loss at a temperature of 259.71° C.±0.5° C. (such as 259.71° C.±0.2° C., in particular 259.71° C.±0.1° C., more particularly 259.71° C.); and/or
(xiii) a thermogravimetric analysis (TGA) thermogram as depicted in FIG. 6 .
12 . A pharmaceutical composition comprising a compound of formula (I) according to any of claims 7 to 11 , in combination with one or more therapeutic agents.
13 . A compound of formula (I) according to any of claims 7 to 11 for use in therapy.
14 . A compound of formula (I) according to any of claims 7 to 11 for use in the prophylaxis or treatment of cancer.
15 . A process for preparing a compound of formula (XX) as defined in claim 1 , which comprises reacting a compound of formula (XVIII):
with a compound of formula (XIX):
16 . The process according to claim 15 , which comprises a suitable catalyst, such as a copper catalyst, in particular copper (I) iodide, and a suitable ligand, such as N,N′-dimethylethylenediamine.
17 . A process for preparing a compound of formula (XVI):
which comprises reacting a compound of formula (XV):
in a single vessel with methyl-d3 iodide in the presence of an inorganic base, such as potassium carbonate, followed by treatment with potassium acetate and further addition of an inorganic base, such as potassium carbonate.
18 . A process for preparing a compound of formula (XIII):
which comprises the use of a compound of formula (II):
as the starting material.
19 . The process according to claim 18 , which comprises the following steps:
20 . A process for preparing a compound of formula (XII) as defined in claim 19 , which comprises reacting a compound of formula (XI) as defined in claim 19 , with suitable oxidants, such as ruthenium dioxide and sodium periodate.
21 . A process for preparing a compound of formula (XI) as defined in claim 19 , which comprises reacting a compound of formula (X) as defined in claim 19 , with suitable oxidants, such as ruthenium trichloride and sodium periodate.
22 . A process for preparing a compound of formula (XII) as defined in claim 19 , which comprises reacting a compound of formula (X) as defined in claim 19 , with suitable oxidants, such as ruthenium trichloride and sodium periodate.
23 . A process for preparing a compound of formula (VIII) as defined in claim 19 , which comprises reacting a compound of formula (VII) as defined in claim 19 , with a suitable acid, such as phosphoric acid.
24 . A process for preparing a compound of formula (V) as defined in claim 19 , which comprises the use of a compound of formula (II) as defined in claim 19 , as the starting material.
25 . The process according to claim 24 , which comprises the following steps:Join the waitlist — get patent alerts
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